It is estimated that in 2004 more than 2.4 million new cancer cases will be diagnosed in the U.S. and more than 1 million are expected to be skin cancers. Of those individuals with skin cancer, 96,000 will be diagnosed with melanoma (4% of newly diagnosed cancers), the most deadly form of skin cancer. Furthermore, the incidence of melanoma continues to increase faster than any other cancer. The stochastic nature of 90 to 95% of all cancers means that everyone is at risk of developing a cancer. In the United States, men have a 50% lifetime risk of developing cancer, while women have a 33% chance (ACS, 2004). With an annual mortality rate of ˜563,700 per year, cancer is the second leading cause of death in the United States.
Vaccination against cancer has been proposed for treatment, and occasionally prevention, of cancer, and considerable research effort has been devoted to the exploration of a variety of cancer vaccination strategies. The goal of finding vaccine compositions and treatment methods that are capable of reliably and predictably overcoming tolerance and setting in motion an immune response against tumor cells without inducing autoimmunity has, until now, proved elusive. It is nevertheless clear that cancerous cells have characteristics that can be recognized by the immune system, as demonstrated by experiments in which mice vaccinated with various kinds of tumor cell preparations show protection from tumor challenge. Antigens that are expressed in or by tumor cells are referred to as “tumor associated antigens” (“TAA's”). A particular TAA may or may not also be expressed in non-cancerous cells; TAA's that are not expressed or rarely expressed in non-cancerous cells, or whose expression in non-cancerous cells is sufficiently reduced in comparison to that in cancerous cells that an immune response induced upon vaccination is reasonably specific to cancerous cells, are referred to as “tumor specific antigens” (“TSA's”).
Over the past two decades, many labs have devised numerous techniques which aim to turn the patient's immune system against a pre-existing tumor (Berzofsky et al., 2004). These include the use of whole cells, peptides, genetically modified tumor cells, heat-shock proteins or apoptotic tumor cells to stimulate the host's immune system to respond to antigens that are characteristic of cancer cells. Arguably the most elegant approach to cancer vaccination is to use vaccine formulations composed of known and defined TAA's, since this will maximize specificity. Functionally, TAA's may be classed as self and non-self Self TAA's are derived from non-mutated genes whose expression is limited to selected normal tissues or to overexpressed proteins. While most TAA's identified to date belong to this self class, there are two large potential problems associated with such antigens: autoimmunity and tolerance. Non-self TAA's are expressed exclusively or predominantly by cancer cells, and can be thought of as tumor-specific antigens (TSA's). TSA's can originate either exogenously (such as those derived from viral proteins in virally-associated tumors) or endogenously. Mutation-derived TSA's can arise from point mutations, translocations, and exon mis-splicing. Unlike self TAA's, TSA's pose greatly reduced risk of autoimmunity and tolerance.